Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2000-08-29

2002-08-27

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S252120, C514S253010, C514S263220, C514S263300, C544S256000, C544S277000, C544S360000

Reexamination Certificate

active

06440982

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDE5). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
PRIOR ART
Certain purinone derivatives for use in inhibition of cGMP PDEs are disclosed in European patent applications EP 722943, EP 722944, EP 293063 and EP 352960, international patent applications WO 96/16657 and WO 94/00453, German patent application DE 19702785 and Japanese patent application JP 63196585. Further, EP 675124 discloses purine derivatives for use as anti-inflammatory agents.
DISCLOSURE OF THE INVENTION
According to a first aspect of the invention there is provided compounds of formulae IA and IB,
wherein
X represents CH or N;
R
1
represents H, —CN, —C(O)N(R
4
)R
5
, —C(O)R
4
, —C(O)OR
4
, —N(R
4
)R
6
, —OR
7
, aryl, Het
2
or lower alkyl (which alkyl group is optionally interrupted by one or more of —O—, —S— or —N(R
4
)— and/or substituted and/or terminated by one or more substituents selected from halo, —CN, —NO
2
, lower alkyl, —C(O)N(R
4
)R
5
, —C(O)R
4
, —C(O)OR
4
, —N(R
4
)R
6
, —OR
7
, —S(O)
n
R
4
, —S(O)
n
N(R
4
)R
5
, aryl and Het
2
);
R
6
represents R
5
, —S(O)
2
R
8
, —S(O)
2
N(R
4
)R
5
, —C(O)R
4
, —C(O)OR
8
or —C(O)N(R
4
)R
5
;
R
7
represents R
4
or —C(O)R
4
;
R
3
, R
4
, R
5
and R
8
independently represent, at each occurrence when used herein, lower alkyl, which alkyl group is optionally substituted and/or terminated by one or more substituents selected from lower alkyl, aryl, Het
3
, halo, —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
2
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
and —N(R
11
)R
9i
;
R
3
, R
4
and R
5
may also, at each occurrence when used herein, independently represent H;
R
4
, R
5
and R8 may also, at each occurrence when used herein, independently represent aryl;
R
2
represents H, aryl, Het
4
or lower alkyl, which latter group is optionally substituted and/or terminated by one or more substituents selected from lower alkyl (which latter group is optionally substituted and/or terminated by one or more substituents selected from —OH and halo), aryl, Het
5
, halo, —CN, —NO
2
, OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
2
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
or —N(R
11
)R
9i
;
R
11
represents, at each occurrence when used herein, H, aryl, lower alkyl (which alkyl group is optionally substituted by one or more substituents selected from aryl and halo), —C(O)R
9j
, —C(O)N(R
9k
)R
9m
or —S(O)
2
R
10b
;
R
9a
to R
9m
independently represent, at each occurrence when used herein, H, aryl or lower alkyl (which alkyl group is optionally substituted by one or more substituents selected from aryl and halo);
R
10a
and R
10b
represent, at each occurrence when used herein, aryl or lower alkyl (which alkyl group is optionally substituted by one or more substituents selected from aryl and halo);
Het
1
represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains at least one nitrogen atom (via which atom the Het
1
group is attached to the rest of the molecule) and, optionally, one or more further heteroatoms selected from nitrogen, oxygen and/or sulfur;
Het
2
to Het
5
independently represent optionally substituted four- to twelve-membered heterocyclic groups, which groups contain one or more heteroatoms selected from nitrogen, oxygen and/or sulfur;
each aryl group is optionally substituted with one or more substituents selected from halo, lower alkyl (which latter group is optionally substituted by one or more substituents selected from —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
2
N(R
9f
)R
9g
, —S(O)
n
R
10a
, —OC(O)R
9h
and —N(R
11
)R
9i
), —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
n
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
and —N(R
11
)R
9i
;
Het
1
, Het
2
, Het
3
, Het
4
and Het
5
are each optionally substituted with one or more substituents selected from lower alkyl (which alkyl group may itself be optionally substituted and/or terminated by one or more substituents selected from lower alkyl, aryl, Het
2
, halo, —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
n
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
and —N(R
11
)R
9i
), aryl, Het
2
, halo, —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
n
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
and —N(R
11
)R
9i
; and
n represents, at each occurrence when used herein, 0, 1 or 2;
or a pharmaceutically, or a veterinarily, acceptable derivative thereof;
provided that when the compound is a compound of formula IB in which:
X represents CH;
R
1
represents H;
R
3
represents C
1-8
alkyl; and
Het
1
represents a 5- or 6-membered saturated heterocyclic ring, which ring is optionally substituted (via a free ring N-atom) by C
1-6
alkyl (which latter group is optionally substituted by —OH);
then R
2
does not represent:
(a) C
3-11
alkyl, which C
3-11
alkyl group is substituted by one of the following:
(i) in the C-1 position (relative to the purinone N-atom), by —C(O)R
9b
(wherein R
9b
represents H or C
1-4
alkyl) or C
1-11
alkyl;
(ii) in the C-2 position (relative to the purinone N-atom) by one group selected from —OR
9a
(wherein R
9a
represents H, C
1-6
alkyl or benzyl), —OC(O)R
9h
(wherein R
9h
represents H, C
1-6
alkyl or phenyl) and —N(R
11
)R
9i
(wherein R
9i
represents H or C
1-6
alkyl and R
11
represents H, C
1-6
alkyl, —C(O)R
9j
(in which R
9j
represents H, C
1-6
alkyl or phenyl) or —S(O)
2
R
10b
(in which R
10b
represents C
1-4
alkyl or phenyl)) and (optionally), at the same C-2 position, by a further C
1-4
alkyl group;
 and which C
3-11
alkyl group is optionally substituted:
(I) in the C-2 to C-11 positions (relative to the purinone N-atom), by phenyl (optionally substituted by halo, —CN, —NO
2
, C
1-6
alkyl or —S(O)
2
N(R
9f
)R
9g
, in which latter group R
9f
and R
9g
independently represent H, phenyl or lower alkyl); and/or
(II) in the C-1 position (relative to the purinone N-atom), by C
1-3
alkyl;
C
3-9
alkyl substituted in the C-2 to C-9 positions (relative to the purinone N-atom) by —N(R
11
)R
9i
(wherein R
11
and R
9i
each independently represent H or C
1-5
alkyl optionally substituted by phenyl, which latter group is substituted by —S(O)2N(R
9f
)R
9g
(in which R
9f
and R
9g
independently represent H, phenyl or lower alkyl)) and optionally substituted in the C-1 position (relative to the purinone N-atom) by:
(i) C
1-5
alkyl (which alkyl group is optionally substituted by —OH); and/or
(ii) C
1-3
alkyl; or
(c) C
1-4
alkyl or C
10-16
n-alkyl;
wherein, in the above proviso, unless otherwise indicated, alkyl, phenyl and benzyl groups are unsubstituted,
which compounds are referred to together hereinafter as “the compounds of the invention”.
The term “aryl”,when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl. Unless otherwise specified, each aryl group identified herein is optionally substituted with one or more substituents selected from halo, lower alkyl (which latter group is optionally substituted by one or more substituents selected from —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
2
N(R
9f
)R
9g
, —S(O)
n
R
10a
, —OC(O)R
9h
and —N(R
11
)R
9i
), —CN, —NO
2
, —OR
9a
, —C(O)R
9b
, —C(O)OR
9c
, —C(O)N(R
9d
)R
9e
, —S(O)
n
R
10a
, —S(O)
2
N(R
9f
)R
9g
, —OC(O)R
9h
, and —N(R
11
)R
9i
(in which n, R
9a
to R
9i
and R
10a
are as hereinbefore defined). When aryl is substituted by a group containing one or more further aryl substituents, then such further aryl substituents may not be substituted by groups containing aryl substituents.
Het (Het
1
, Het
2
, Het
3
, Het
4
, Het
5
) groups may be fully saturated, partly

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